Lamotrigine for bipolar disorder and comorbid cocaine dependence: A replication and extension study

Method Participants received a baseline evaluation and assessment for up to 36 weeks with the 17-item Hamilton Rating Scale for Depression (HRSD 17 ), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS 18 ), and Cocaine Craving Questionnaire (CCQ). Urine samples were obtained, and participants reported drug use during the previous week. Results In the replication sample ( n = 32), significant improvements were observed in HRSD 17 , YMRS, BPRS 18 , and CCQ (baseline to exit), as well as on dollars/week spent on cocaine. In the extension study, the original sample ( n = 30) and the replication sample ( n = 32) were combined for a total of 62 participants in the intent-to-treat sample. HRSD 17 , YMRS, BPRS 18 , and CCQ scores, as well as dollars spent on cocaine, decreased significantly. Limitations The study has an open-label, uncontrolled design. Conclusion Lamotrigine treatment was associated with significant improvements in mood, drug craving, and drug use. Controlled trials are needed. Keywords Lamotrigine Bipolar disorder Cocaine Mania Depression 1 Introduction Regier et al. (1990) found a 61% and 48% prevalence of substance abuse in people with bipolar I and II disorders (BPD), respectively. However, few medication trials have specifically examined patients with BPD and cocaine-related disorders. We gave quetiapine to 17 patients with BPD and cocaine dependence, finding significant improvement in mood and craving, and trends toward decreases in cocaine use ( Brown et al., 2002 ). Camacho and Akiskal (2005) reported substantial improvement in mood symptoms and drug craving, following the addition of mood stabilizing anticonvulsants, in patients with stimulant abuse and cyclothymic disorder or other bipolar spectrum disorders who had been previously refractory to drug abuse treatment. Lamotrigine has efficacy for mood symptoms in BPD ( Calabrese et al., 1999, 2000, 2003; Bowden et al., 2003 ). An open-label study found significant reductions in cocaine use and craving in HIV-positive patients with cocaine dependence given lamotrigine ( Margolin et al., 1998 ). We reported significant improvement in mood, craving, and a trend toward a decrease in cocaine use in 30 patients with BPD and cocaine dependence given open-label lamotrigine ( Brown et al., 2003 ). This report replicates our earlier findings with lamotrigine in outpatients with BPD and cocaine dependence in an open-label trial of 12 weeks of lamotrigine therapy (replication sample). We extend our previous findings by 1) analyzing data pooled from the earlier report ( n = 30) and the present report to include 62 with ≥ 1 postbaseline visit, 2) by including maintenance data for up to 24 additional weeks, and 3) by exploring predictors of response. Our primary aim was to examine change in cocaine use, but cocaine craving and psychiatric symptoms were also examined. 2 Methods 2.1 Participants Outpatients with BPD and cocaine dependence ( n = 73 at baseline) participated in a 36-week, open-label study using lamotrigine with weekly assessment for 12 weeks followed by assessments every 4 weeks for an additional 24 weeks. Participants provided written consent as approved by the UT Southwestern Institutional Review Board. Inclusion criteria included age of 18–65 years, diagnosis of bipolar I, II, or NOS disorder, and cocaine dependence within 3 months prior to entry. Outcome data on acute treatment (first 12 weeks) on the first 33 participants (30 in intent-to-treat sample [ITT]) with BPD and cocaine dependence have been previously reported ( Brown et al., 2003 ). In this report, additional participants ( n = 32 in ITT sample) are analyzed in the same fashion as in the prior report to replicate those findings. In a second analysis, data from the entire group ( n = 62 in ITT sample), including data from a 24-week maintenance phase, are reported, and predictors of response are explored to extend findings from our initial report. 2.2 Psychiatric and drug assessments At baseline, the Mini International Neuropsychiatric Interview (MINI) ( Sheehan et al., 1998 ) was conducted to confirm diagnoses. At baseline and every visit, participants were assessed with the Hamilton Rating Scale for Depression (HRSD 17 ) ( Hamilton, 1960, 1967 ), Young Mania Rating Scale (YMRS) ( Young et al., 1978 ), 18-item Brief Psychiatric Rating Scale (BPRS 18 ) ( Overall and Gorham, 1962 ), and Cocaine Craving Questionnaire (CCQ) ( Tiffany et al., 1993 ). Drug use was determined by self-report of dollars and days of drug use in the past week, and urine drug screens (UDS). 2.3 Medication dosing and monitoring Lamotrigine was either added to current medication regimens or given as monotherapy. No scheduled psychotropic medication had been initiated within 4 weeks of initiating lamotrigine therapy. A slow titration of lamotrigine (25 mg/d for 2 weeks, 50 mg/d for 2 weeks, then 75 mg for 1 week, 100 mg for 1 week, then weekly increases of 50 up to 300 mg) was used. A slower titration was used for the 10 patients taking valproate (12.5 mg/d for 2 weeks then 25 mg/d for 2 weeks). No participants were taking carbamazepine. 2.4 Statistical analyses In the replication study, baseline to exit changes in BPRS 18 , YMRS, HRSD 17 , CCQ, and dollar and days/week of cocaine use were analyzed using paired Student's t -tests (last observation carried forward) on participants who completed the baseline evaluation and at least one postbaseline assessment (ITT sample), as in our earlier report. For the extension study, pooled data were analyzed as above. Baseline and exit urine drug screens were analyzed using McNemar's test, which evaluates significance of changes in paired, dichotomous data with binomial distributions. Correlations between changes in HRSD 17 , YMRS, and BPRS 18 scores, CCQ scores, dollars spent on drugs, and days of drug use were examined using Pearson's correlation coefficient. 3 Results Demographic information is provided in Table 1 . Concomitant medications included antidepressants ( n = 27), sedative/hypnotic/anxiolytics ( n = 16), antipsychotics ( n = 12), anticonvulsants ( n = 12), lithium ( n = 4), and naltrexone ( n = 1). Twenty-three participants were on no other medications at baseline. Mean number of concomitant psychotropic medications was 1.47 ± 1.49 per participant at baseline and 1.47 ± 1.50 at exit. Concomitant medication changes during the study included the addition of sedative/hypnotic/anxiolytics ( n = 6), antidepressants ( n = 4), antipsychotics ( n = 1), or anticonvulsants ( n = 1); the discontinuation of antidepressants ( n = 3), antipsychotics ( n = 1), or anticonvulsants ( n = 1); and change in dosage of anticonvulsants ( n = 2), antidepressants ( n = 1), or sedative/hypnotic/anxiolytics ( n = 1). For the replication study, 40 participants with BPD and cocaine dependence were enrolled. Of these, 32 returned for at least one postbaseline assessment (ITT sample), and their data were analyzed using the methods in our previous report. HRSD 17 , YMRS, and BPRS 18 scores, CCQ scores, and dollars/week spent on cocaine significantly decreased during lamotrigine therapy ( Table 2 ). Days of cocaine use and number of positive urine cocaine screens did not change significantly ( p = ns). In the extension study, 73 participants were enrolled. Eleven patients did not return after the baseline evaluation; thus, 62 patients were used in the ITT analysis ( Table 3 ). The mean weeks of study participation was 8.2 ± 7.6 (range 1–36 weeks). The mean exit dose of lamotrigine was 154.8 ± 114.4 mg/day in those ( n = 52) not taking valproate and 130.0 ± 128.9 mg/day in those ( n = 10) taking valproate. In the entire sample HRSD 17 , YMRS, and BPRS 18 scores, CCQ scores, and dollars/week of cocaine use, but not days of cocaine use, decreased significantly. At baseline 27% of urine samples were positive which decreased non-significantly to 23% while receiving lamotrigine ( p = ns). In the subset ( n = 36) with a manic/hypomanic or mixed mood state at baseline YMRS score decreased from 16.5 ± 5.9 to 11.2 ± 5.0 ( p < 0.001). In the subset ( n = 43) with depressed or mixed mood states at baseline HRSD 17 scores decreased from 19.7 ± 5.4 to 13.1 ± 7.5 ( p < 0.001). In the extension study ITT sample ( n = 62), relationships between change in psychiatric symptom severity and cocaine use/craving were explored. Changes in HRSD 17 ( r = 0.29, p = 0.024) and BPRS 18 ( r = 0.28, p = 0.032) showed significant correlations with CCQ changes. HRSD 17 ( r = 0.34, p = 0.009) and BPRS 18 ( r = 0.35, p = 0.006) scores correlated significantly with change in days/week of cocaine use. Change in BPRS 18 scores showed a significant correlation with change in dollars spent on cocaine ( r = 0.29, p = 0.024). The extension sample ( n = 62) was divided by diagnosis, gender, concomitant medications, and mood state to explore response predictors. Women ( n = 33 in ITT sample) had significantly greater decreases in CCQ scores than men (− 17.1 ± 14.9 vs. − 5.7 ± 16.9, p = 0.007) but no other gender differences were found. Presence ( n = 37) or absence of antisocial personality, disorder concomitant psychiatric medications at baseline ( n = 39), or change in concomitant medications during the study ( n = 19) did appear to have a significant impact on outcomes. To our knowledge no participants withdrew secondary to side effects. Four participants developed rashes, none of which were severe or clearly related to lamotrigine. None of the participants with rashes were taking valproate. All developed the rashes within 4 weeks of staring lamotrigine and were discontinued from the study. One of these patients was seen by a dermatologist who said it was an allergic reaction and prescribed steroid cream. In three of the cases the rashes were improved or had resolved at follow-up. One patient was lost to follow-up. 4 Discussion Our previous findings ( Brown et al., 2003 ) were replicated in a new sample of 32 participants. Lamotrigine was associated with improvement in manic and depressive symptoms, reduction in cocaine craving and use, and was potentially useful for patients with BPD and cocaine-related disorders. In the extension study, lamotrigine was associated with a reduction in craving for and self-reported use of cocaine. Positive urine drug screens did not change significantly during the study perhaps because of the infrequency of positive urine drug screens at baseline and cocaine metabolites are only detectable in the urine for 2–3 days. Interestingly, amount of self-reported cocaine use appeared to show a greater decrease during the study than days of cocaine use. This finding suggests that participants may have used a smaller amount of cocaine rather than decrease the frequency of cocaine use. Changes in psychiatric symptom severity, particularly depression, in some cases showed significant relationships with change in cocaine use/craving. Thus, improvements in psychiatric symptoms during lamotrigine therapy may lead to a reduction in drug use/craving. To our knowledge, this is the largest study conducted in persons with BPD and substance dependence. The study examines effectiveness of lamotrigine in a “real world” clinical population of patients with both bipolar disorder and substance dependence. Larger, controlled studies of lamotrigine in this population are needed. Acknowledgements Supported in part by the Stanley Medical Research Institute Bipolar Disorder Center at UT Southwestern Medical Center. Study medication provided by GlaxoSmithKline. References Bowden et al., 2003 C.L. Bowden J.R. Calabrese G. Sachs L.N. Yatham S. Akthar Asghar M. Hompland P. Montgomery N. Earl T.M. Smoot J. DeVeaugh-Geiss A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder Arch. Gen. Psychiatry 60 2003 392 400 Brown et al., 2002 E.S. 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